Study of the modulatory activity of BZ (omega) receptor ligands on defensive behaviors in mice: Evaluation of the importance of intrinsic efficacy and receptor subtype selectivity

1. This study examined the hypothesis that the anxiolytic effects of benzod iazepine (BZ (omega)) receptor ligands may be associated with actions at a defined receptor subtype and/or their level of intrinsic activity using the mouse defense test battery. 2. This test has been designed to assess defensive reactions of Swiss mice confronted with a natural threat (a rat) and situations associated with thi s threat. Primary measures taken before, during and after rat confrontation were escape attempts, flight, risk assessment and defensive threat and att ack. 3. The drugs used were the non-selective BZ (omega) receptor full agonist d iazepam, the non-selective BZ (omega) receptor partial agonist bretazenil a nd the beta-carboline abecarnil which acts as a full agonist on GABA(A) rec eptors containing the alpha 1- and the alpha 3-subunits and as a partial ag onist at receptors containing the alpha 2- and the alpha 5-subunits. The dr ugs were given alone and diazepam was co-administered with either bretazeni l or abecarnil. 4. When administered alone, diazepam attenuated several defensive responses including risk assessment activities, defensive threat/attack reactions up on forced contact with the rat and escape attempts following the removal of the rat from the apparatus. Unlike diazepam, bretazenil was devoid of sign ificant activity on defense and abecarnil displayed depressant activity. 5. Bretazenil blocked all behavioral effects of diazepam on defense behavio rs. The coadministration of diazepam and abecarnil produced a behavioral pr ofile similar to that observed when diazepam was administered alone, indica ting that abecarnil did not influence the effects of diazepam on defense. B y contrast, diazepam completely antagonized the sedative effects of abecarn il. 6. These findings indicate that only BZ (omega) ligands with high intrinsic efficacy at all BZ (omega) receptor subtypes display clear and specific ef fects on defensive behaviors in mice, and suggest that GABA(A) receptors co ntaining the alpha 3 subunit might represent the primary target involved in the modulatory action of diazepam on defensive behaviors.